This invention relates to compounds having a physiological cooling effect on the skin and on the mucous membranes of the body, particularly those of the mouth, nose and throat.
Menthol exists abundantly in nature and has been known for a long time as a physiological cooling compound. It is well established that the “cooling” effect of menthol is a physiological effect due to the direct action of menthol on the nerve ends of the human body responsible for the detection of hot or cold and is not due to latent heat of evaporation or dissolution. Menthol has been used widely in cigarettes, cosmetics, toothpastes, chewing gum, sweets, and medicines. Disadvantages of menthol include its strong “stinging” smell, bitter taste, burning sensation in high concentration and high volatility. These undesirable properties limit applications of menthol to some extent.
Since 1960's, researchers have been working on discovering synthetic substitutes of menthol, which possess low volatility and have almost no odor or taste.
The easiest and most straightforward direct modification of l-menthol is to make menthyl esters, such as, menthyl acetate, menthyl lactate (German Patent 2,608,226), saccharide ester of menthol (Swiss Patent 484,032), menthyl 2-hydroxybutyrate (French Patent 2,577,922), menthyl monomenthyl succinate (U.S. Pat. No. 3,111,127), monomenthyl glutarate (U.S. Pat. No. 6,365,215), menthyl hydroxyethyl carbonate (U.S. Pat. No. 3,419,543), etc. Another way to take advantage of hydroxyl group in menthol is to incorporate it to an ether linkage, e.g., menthyl glyceryl ether (U.S. Pat. No. 4,459,425). Ketals of menthone, such as, menthone glycerin ketal can be made readily and it is proven to be a coolant (German Patent 4,266,043 and U.S. Pat. No. 5,266,592) because of the paramenthane moiety in the structure. Menthol analogs are equally attractive, such as, isopulegol (U.S. Pat. No. 5,773,410) and paramenthane-3,8-diol (U.S. Pat. No. 5,959,161). Both compounds are obtained by cyclization of citronellal.
A large variety of compounds without paramenthane structure have also been found to possess cooling property, for instance, cyclohexanol derivatives (German Patent 2,317,000), cyclic secondary and tertiary alcohols (GB Patent 1,404,596), alkylmethanols (German Patent 2,439,770), trialkylphospine oxides (German Patent 2,345,156), cyclic and acyclic sulfoxides and sulfones (German Patent 2,334,985 and German Patent 2,336,495) all show cooling effect, but the strength of the cooling effect varies.
Amides, as cooling agents, might be the most important group of compounds. N,N-dimethyl 2-ethylbutanamide and 2,2-deimethylpropanamide (French Patent 1,572,332) were found to possess physiological cooling effect decades ago. Later on, a large number of cyclic amides with 5- to 11-membered rings (GB Patent 1,489,359, GB Patent 1,489,359, German Patent 2,624,504 and U.S. Pat. No. 4,296,093) were identified as cooling agents. Later, menthol derived amides (U.S. Pat. No. 4,150,052) were discovered as coolants by Wilkinson Sword company. Among these amides, N-ethyl menthane-carboxamide (WS-3) was successfully commercialized.
In 1972 Wilkinson Sword also discovered another attractive series of acyclic amides (2,3-dimethyl-2-isopropylbutyramides, GB 1,421,744), which interestingly do not show much similarity in structure to menthol or menthol derivatives. Of all these amides of highly branched, tertiary acyclic carboxylic acids, N,2,3-trimethyl-2-isopropylbutyramide (WS-23) has been successfully commercialized. WS-23 possesses a strong cooling effect and a good taste quality.
A new current trend is searching for convenient liquid sellable forms of cooling agents with little or no solvent. To find eutectic mixtures of existing cooling agents requires cooling compounds with low melting points and even liquid cooling compounds with comparable cooling effect. Primary amides, e.g. WS-23, with high enough molecular weight are normally highly crystalline due to the intermolecular hydrogen bonding in the structure. Introducing functional groups with oxygen atom in either ether linkage or terminal hydroxyls will promote intramolecular hydrogen bonding, thus lowering intermolecular hydrogen bonding and also affecting packing of those molecules. Therefore it lowers the crystallinity of the compounds, resulting in lower melting points.
It is an object of the present invention to provide new compounds with pronounced physiological cooling effect without the disadvantage of strong odors and bitter taste.
It is also a further object of this invention to provide compounds with pronounced physiological cooling effect and relatively low melting points to provide the possibility of liquid coolants or coolant mixtures.